WO1996009048A1 - Use of 2,4-diamino pyrimidine 3-oxide or a salt thereof for treating collagen maturation and structuring disorders - Google Patents

Use of 2,4-diamino pyrimidine 3-oxide or a salt thereof for treating collagen maturation and structuring disorders Download PDF

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Publication number
WO1996009048A1
WO1996009048A1 PCT/FR1995/001197 FR9501197W WO9609048A1 WO 1996009048 A1 WO1996009048 A1 WO 1996009048A1 FR 9501197 W FR9501197 W FR 9501197W WO 9609048 A1 WO9609048 A1 WO 9609048A1
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WO
WIPO (PCT)
Prior art keywords
composition
dpo
use according
proportion
collagen
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PCT/FR1995/001197
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French (fr)
Inventor
Yann Mahe
Lionel Breton
Jean-Baptiste Galey
Bruno Bernard
Original Assignee
L'oreal
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Publication date
Priority to AT95931260T priority Critical patent/ATE213414T1/en
Priority to AU34765/95A priority patent/AU691336B2/en
Priority to CZ97842A priority patent/CZ284476B6/en
Priority to JP8510645A priority patent/JP2945482B2/en
Priority to US08/809,950 priority patent/US5846552A/en
Priority to PL95319279A priority patent/PL186385B1/en
Priority to MX9701996A priority patent/MX9701996A/en
Priority to HU9701236A priority patent/HU223143B1/en
Application filed by L'oreal filed Critical L'oreal
Priority to BR9508841A priority patent/BR9508841A/en
Priority to CA002199995A priority patent/CA2199995C/en
Priority to EP95931260A priority patent/EP0783307B1/en
Priority to DE69525539T priority patent/DE69525539T2/en
Priority to KR1019970701754A priority patent/KR100250939B1/en
Priority to DK95931260T priority patent/DK0783307T3/en
Publication of WO1996009048A1 publication Critical patent/WO1996009048A1/en
Priority to NO19971182A priority patent/NO311784B1/en
Priority to FI971127A priority patent/FI971127A0/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses

Definitions

  • the subject of the present invention is the use, as active substance, of 2,4-diamino pyrimidine 3-oxide or of one of its salts for the preparation of a therapeutic composition, for pharmaceutical or veterinary use, intended to the treatment of disorders of maturation and structuring of collagen.
  • Minoxidil namely 2,4-diamino-6-piperidino pyrimidine 3-oxide, already described and used in the treatment of certain hypertensions and in the treatment of androgenic alopecia, has been the subject of numerous studies.
  • 2,4-diamino pyrimidine 3-oxide or 2,4-DPO (in the following), although not comprising a tertiary amino group in para of the N-oxide function of the 2,4-diamino pyrimidine ring, made it possible to specifically inhibit lysyl hydroxylase.
  • This compound has already been described in WO-92/01437 as an active agent intended for the cosmetic treatment, by topical application, of hair loss.
  • 2,4-DPO has no anti-hypertensive effect and therefore has a particularly satisfactory safety, while having an inhibitory activity on lysyl hydroxylase equal to or even superior to that of Minoxidil.
  • the present invention therefore relates to the use, as active substance of 2,4-DPO or one of its salts for the preparation of a therapeutic composition, for pharmaceutical or veterinary use, intended for the treatment of disorders collagen maturation in humans or animals.
  • collagen maturation disorder is understood to mean, according to the invention, any unwanted accumulation of collagen, and in particular any disorder in the structure of the collagen matrix of the skin tissue or of the ocular conjunctiva; these disorders can be of spontaneous, traumatic or post-operative origin.
  • these disorders there may be mentioned in particular vitreoretinopathies, systemic scleroderma, skin thickening induced by ultraviolet rays and scar keloids.
  • 2,4-DPO makes it possible in particular to obtain an aesthetic improvement of the patient treated.
  • the treatment can be curative, it is nevertheless preferably used in a preventive manner, that is to say during the period during which the structuring occurs and, consequently, the accumulation of collagen, this taking place in particular during the healing period.
  • 2,4-DPO can be used for the preparation of a therapeutic composition in a form which can be administered topically, transdermally or intradermally.
  • physiologically acceptable salts is meant according to the invention, addition salts of an acid such as those of sulfuric, hydrochloric, phosphoric, acetic, benzoic, salicylic, glycolic, aceturic, succinic, nicotinic, tartaric acid. , maleic, methane sulfonic, picric and lactic.
  • an acid such as those of sulfuric, hydrochloric, phosphoric, acetic, benzoic, salicylic, glycolic, aceturic, succinic, nicotinic, tartaric acid.
  • maleic, methane sulfonic, picric and lactic is generally between 0.0001 and 5% by weight, and preferably between 0.01 and 2% by weight relative the total weight of the composition.
  • the vehicle can be very varied in nature but is preferably a physiologically acceptable medium for topical application, of course compatible with the active substance.
  • 2,4-DPO can be found in this medium either in the dissolved state or in the dispersed state, in particular in micronized form.
  • the physiologically acceptable medium can consist of water or a mixture of water and a solvent or a mixture of solvents.
  • solvents which can be used, mention may in particular be made of lower C r C 4 alcohols such as ethanol, isopropanol, tert-butanol, alkylene glycols, alkylene glycol and dialkylene glycol alkyl ethers such as monoethyl ether d ethylene glycol, propylene glycol monomethyl ether, diethylene glycol monoethyl ether.
  • These compositions intended for topical application can also contain at least one conventional additive or an active principle.
  • UV.A and UV.B filters such as methoxycinnamates and benzophenone derivatives, antioxidants and / or free radical scavengers such as DMSO, ⁇ -tocopherol, BHA, BHT, superoxide dismutase, hydrating agents such as urea, glycerin, lactic acid, hydroxy acids, thiamorpholinone and its derivatives and pyrrolidone carboxylic acid derivatives, in particular its sodium and potassium, steroidal and non-steroidal anti-inflammatory agents such as hydrocortisone, ⁇ -methasone, dexamethasone, acetyl salicylic acid, indomethacin, isoprofen, vitamin D or niflumic acid, and antibacterials such as those belonging to the group of macrolides, pyranosides and tetracyclines such as erythromycin.
  • UV.A and UV.B filters such as methoxycinnamates and benzophenone derivatives,
  • compositions may also contain preservatives, stabilizers, pH regulators, osmotic pressure modifiers and emulsifiers.
  • compositions intended for topical application based on 2,4-DPO can be presented in different forms such as for example in the form of lotions, gels, mousses, vesicular dispersions, sprays or aerosol mousses.
  • compositions can also be in the form of gelled or thickened compositions.
  • gelled compositions mention may in particular be made of those which are essentially aqueous, gelled with heterobiopolysaccharides such as xanthan gum, scleroglucans or cellulose derivatives and in particular cellulose ethers, or hydroalcoholic compositions gelled with polyhydroxyethylacrylates or methacrylates.
  • thickened aqueous compositions there may be mentioned those obtained in particular using a polyacrylic acid crosslinked with a polyfunctional agent such as those sold under the names of "Carbopol®" by the company Goodrich. It is however of course possible to use as thickening agent any agent usually used in pharmacy or dermo-pharm acie.
  • 2,4-DPO is generally applied to the parts of the body to be treated at a rate of 0.0001 to 5 mg / kg / day and preferably from 0.001 to 1 mg / kg / day.
  • the treatment is generally continued throughout the period during which the accumulation of collagen occurs and may possibly be continued for 90 days after this.
  • 2,4-DPO for the preparation of therapeutic compositions intended for administration by transdermal route.
  • the proportion of 2,4-DPO is then generally between 0.001 and 5% and preferably between 0.01 and 2% relative to the total weight of the composition.
  • the excipient used in these compositions is generally chosen from vinyl copolymers or copolymers, optionally added with a penetration promoter.
  • compositions intended for transdermal application can in particular be administered using a self-adhesive system adhering to the skin and ensuring the continuous passage, for at least 24 hours, of a controlled quantity of active substance, through the skin, into the bloodstream.
  • 2,4-DPO can also be used for the preparation of therapeutic compositions intended for administration by the intradermal route.
  • the proportion of 2,4-DPO is then generally between 0.0001 and 5% by weight, and preferably between 0.01 and 1% by weight relative to the total weight of the composition. 2,4-DPO is then in soluble form in a physiologically acceptable vehicle such as physiological saline.
  • compositions intended for intradermal administration can also comprise various therapeutic agents such as, for example, antibacterial agents, antioxidant agents and anti-inflammatory drugs, steroid and non-steroid.
  • 2,4-DPO is generally administered intradermally at a dose less than or equal to 5 mg / kg / day, and preferably between 0.0001 and 1 mg / kg / day.
  • the treatment is generally applied during the entire period during which the accumulation of collagen occurs and can possibly be continued for 30 days after this.
  • compositions intended for pharmaceutical use can be formulated in a form more suitable for veterinary use, especially in the treatment of equines such than the horse.
  • the compositions according to the invention are prepared according to known methods.
  • fibroblasts are seeded in a 60 mm diameter petri dish containing a Dulbecco modified culture medium supplemented with a culture of fibroblasts originating from external connective sheaths of human hair on the fifth subculture.
  • a Dulbecco modified culture medium supplemented with a culture of fibroblasts originating from external connective sheaths of human hair on the fifth subculture.
  • 2 mM L-glutamine, 1 mM sodium pyruvate 100 units / ml of penicillin G, 100 ⁇ g / ml of streptomycin S, 250 mg / ml of amphoterine and 10% fetal calf serum marketed by the Company Gibco BRL.
  • FIG. 1A Incubated at 37 ° C. for 3 hours (FIG. 1A) or 18 hours (FIG. 1B) in the presence of 5 M of Minoxidil, 5 mM of 2,4-DPO or 5 mM of Minoxidil sulfate.
  • the total RNA of each of the cell preparations is extracted and then quantified thereof by UV spectrophotometric measurements at 280 nm.
  • RNAs are amplified by a polymerase chain reaction (PCR).
  • PCR polymerase chain reaction
  • complementary DNA is synthesized in vitro using a reverse transcription kit marketed under the name of "First Strand C-DNA Synthesis kit" by Pharmacia LKB Biotechnology AB.
  • the relative expression levels of the mRNAs coding for lysyl hydroxylase and for prolyl hydroxylase are also measured after 3 hours and 18 hours of fibroblast culture in the absence of any treatment.
  • the relative expression rate of the mRNAs coding for the lysyl hydroxylase is 0.55.
  • 2,4-DPO therefore inhibits the expression of mRNAs coding for lysyl hydroxylase more than Minoxidil or its sulphated analogue.
  • the relative expression levels of the mRNAs coding for prolyl hydroxylase are 1.6, 1.3 and 1.15 respectively.
  • the cells are lysed by hypoosmotic shock and the deposition of collagen is fixed with a 5% solution of glutaraldehyde.
  • the fibroblast extracellular matrix is then observed using a scanning electron microscope.
  • the extracellular matrix of a primary culture of untreated fibroblasts is also observed by scanning electron microscopy.
  • a dermal cream is prepared by mixing the following ingredients:
  • a dermal lotion to be sprayed is prepared by mixing the following ingredients:
  • An injectable solution is prepared intradermally by mixing the following ingredients:

Abstract

The use of 2,4-diamino pyrimidine 3-oxide or a physiologically acceptable salt thereof as the active substance for the preparation of a therapeutical composition is disclosed. Said therapeutical composition is useful for treating collagen maturation and structuring disorders.

Description

Utilisation du 2.4-diamino pyrimidine 3-oxyde ou de l'un de ses sels dans le traitement des désordres de la maturation et de la structuration du collagène. Use of 2,4-diamino pyrimidine 3-oxide or one of its salts in the treatment of disorders of maturation and structuring of collagen.
La présente invention a pour objet l'utilisation, en tant que substance active, du 2,4-diamino pyrimidine 3-oxyde ou de l'un de ses sels pour la préparation d'une composition thérapeutique, à usage pharmaceutique ou vétérinaire, destinée au traitement des désordres de la maturation et de la structuration du collagène.The subject of the present invention is the use, as active substance, of 2,4-diamino pyrimidine 3-oxide or of one of its salts for the preparation of a therapeutic composition, for pharmaceutical or veterinary use, intended to the treatment of disorders of maturation and structuring of collagen.
L'obtention de faisceaux de procollagène natif requiert l'hydroxylation d'un certain nombre de résidus prolyl et lysyl du préprocollagène au sein du réticulum endoplasmique rugueux, puis la glycosylation des résidus hydroxy-lysyls dans l'appareil de Golgi. Cette maturation du collagène a fait l'objet de nombreuses études.Obtaining native procollagen bundles requires the hydroxylation of a number of prolyl and lysyl residues of the preprocollagen within the rough endoplasmic reticulum, followed by the glycosylation of the hydroxy-lysyl residues in the Golgi apparatus. This maturation of collagen has been the subject of numerous studies.
Ainsi, le Minoxidil, à savoir le 2,4-diamino-6-pipéridino pyrimidine 3-oxyde, déjà décrit et utilisé dans le traitement de certaines hypertensions et dans le traitement de l'alopécie androgénique, a fait l'objet de nombreuses études en tant qu'inhibiteur spécifique de la lysyl hydroxylase, enzyme intervenant dans la maturation du collagène.Minoxidil, namely 2,4-diamino-6-piperidino pyrimidine 3-oxide, already described and used in the treatment of certain hypertensions and in the treatment of androgenic alopecia, has been the subject of numerous studies. as a specific inhibitor of lysyl hydroxylase, an enzyme involved in the maturation of collagen.
A ce sujet, les études de Murad et al. publiées dans Arch. of Biochem. Biophys., Vol.292, n°l, p.234-238 (1992) et Vol.308, n°l, p.42-47 (1994), ont en effet permis de montrer que la capacité à inhiber la lysyl hydroxylase nécessitait la présence d'un groupe aminé tertiaire situé en para de la fonction N-oxyde du noyau 2,4-diamino pyrimidine et que de préférence, ce groupe devait être un groupe pipéridine comme dans le Minoxidil.On this subject, the studies of Murad et al. published in Arch. of Biochem. Biophys., Vol. 292, no. 1, p. 234-238 (1992) and Vol. 308, no. 1, p. 42-47 (1994), have indeed shown that the ability to inhibit lysyl hydroxylase required the presence of a tertiary amino group located in para of the N-oxide function of the 2,4-diamino pyrimidine nucleus and that preferably this group should be a piperidine group as in Minoxidil.
Or, on a maintenant constaté de façon surprenante et tout à fait inattendue que le 2,4-diamino pyrimidine 3-oxyde ou 2,4-DPO (dans la suite), bien que ne comportant pas de groupe aminé tertiaire en para de la fonction N-oxyde du noyau 2,4-diamino pyrimidine, permettait d'inhiber de façon spécifique la lysyl hydroxylase. Ce composé a déjà été décrit dans WO-92/01437 en tant qu'agent actif destiné au traitement cosmétique, par application topique, de la chute des cheveux. Cependant, contrairement au Minoxidil, le 2,4-DPO ne possède aucun effet anti-hypertenseur et présente donc une innocuité particulièrement satisfaisante, tout en ayant une activité inhibitrice de la lysyl hydroxylase égale voire même supérieure à celle du Minoxidil. La présente invention a donc pour objet l'utilisation, en tant que substance active du 2,4-DPO ou de l'un de ses sels pour la préparation d'une composition thérapeutique, à usage pharmaceutique ou vétérinaire, destinée au traitement des désordres de la maturation du collagène chez l'homme ou chez l'animal.Now, it has now been found, surprisingly and completely unexpectedly, that 2,4-diamino pyrimidine 3-oxide or 2,4-DPO (in the following), although not comprising a tertiary amino group in para of the N-oxide function of the 2,4-diamino pyrimidine ring, made it possible to specifically inhibit lysyl hydroxylase. This compound has already been described in WO-92/01437 as an active agent intended for the cosmetic treatment, by topical application, of hair loss. However, unlike Minoxidil, 2,4-DPO has no anti-hypertensive effect and therefore has a particularly satisfactory safety, while having an inhibitory activity on lysyl hydroxylase equal to or even superior to that of Minoxidil. The present invention therefore relates to the use, as active substance of 2,4-DPO or one of its salts for the preparation of a therapeutic composition, for pharmaceutical or veterinary use, intended for the treatment of disorders collagen maturation in humans or animals.
Dans la suite, l'expression "2,4-DPO" signifiera non seulement le 2,4-DPO lui-même mais également l'un de ses sels tels que définis ci-après. Par désordre de la maturation du collagène, on doit entendre selon l'invention, toute accumulation non désirée de collagène, et notamment, tout désordre de la structure de la matrice collagénique du tissu cutané ou de la conjonctive oculaire ; ces désordres peuvent être d'origine spontanée, traumatique ou post-opératoire. Parmi ces désordres, on peut notamment citer les vitréorétinopathies, les sclérodermites systémiques, les épaississements cutanés induits par les ultra-violets et les chéloïdes cicatriciels.In the following, the expression "2,4-DPO" will mean not only 2,4-DPO itself but also one of its salts as defined below. The term “collagen maturation disorder” is understood to mean, according to the invention, any unwanted accumulation of collagen, and in particular any disorder in the structure of the collagen matrix of the skin tissue or of the ocular conjunctiva; these disorders can be of spontaneous, traumatic or post-operative origin. Among these disorders, there may be mentioned in particular vitreoretinopathies, systemic scleroderma, skin thickening induced by ultraviolet rays and scar keloids.
L'utilisation du 2,4-DPO selon l'invention permet donc d'obtenir notamment une amélioration esthétique du patient traité.The use of 2,4-DPO according to the invention therefore makes it possible in particular to obtain an aesthetic improvement of the patient treated.
Si, selon l'invention, le traitement peut être curatif, il est néanmoins de préférence utilisé de façon préventive, c'est-à-dire au cours de la période durant laquelle se produit la structuration et, par conséquent, l'accumulation de collagène, ceci ayant lieu notamment pendant la période de cicatrisation.If, according to the invention, the treatment can be curative, it is nevertheless preferably used in a preventive manner, that is to say during the period during which the structuring occurs and, consequently, the accumulation of collagen, this taking place in particular during the healing period.
Le 2,4-DPO peut être utilisé pour la préparation d'une composition thérapeutique se présentant sous une forme administrable par voie topique, transdermique ou intradermique.2,4-DPO can be used for the preparation of a therapeutic composition in a form which can be administered topically, transdermally or intradermally.
Par sels physiologiquement acceptables, on doit entendre selon l'invention, des sels d'addition d'un acide tels que ceux de l'acide sulfurique, chlorhydrique, phosphorique, acétique, benzoïque, salicylique, glycolique, acéturique, succinique, nicotinique, tartrique, maléïque, méthane sulfonique, picrique et lactique. Lorsque la composition thérapeutique se présente sous une forme administrable par voie topique, la proportion en 2,4-DPO est généralement comprise entre 0,0001 et 5 % en poids, et de préférence comprise entre 0,01 et 2 % en poids par rapport au poids total de la composition.By physiologically acceptable salts is meant according to the invention, addition salts of an acid such as those of sulfuric, hydrochloric, phosphoric, acetic, benzoic, salicylic, glycolic, aceturic, succinic, nicotinic, tartaric acid. , maleic, methane sulfonic, picric and lactic. When the therapeutic composition is in a form which can be administered topically, the proportion of 2,4-DPO is generally between 0.0001 and 5% by weight, and preferably between 0.01 and 2% by weight relative the total weight of the composition.
Le véhicule peut être de nature très variée mais est de préférence un milieu physiologiquement acceptable pour une application topique, compatible bien entendu avec la substance active.The vehicle can be very varied in nature but is preferably a physiologically acceptable medium for topical application, of course compatible with the active substance.
Le 2,4-DPO peut se trouver dans ce milieu soit à l'état dissous, soit à l'état dispersé, notamment sous forme micronisée.2,4-DPO can be found in this medium either in the dissolved state or in the dispersed state, in particular in micronized form.
Le milieu physiologiquement acceptable peut être constitué par de l'eau ou un mélange d'eau et d'un solvant ou un mélange de solvants. Parmi les solvants pouvant être utilisés, on peut citer notamment les alcools inférieurs en CrC4 comme l'éthanol, l'isopropanol, le tertiobutanol, les alkylène glycols, les alkyléthers d'alkylène glycol et de dialkylène glycol tels que le monoéthyléther d'éthylène glycol, le monométhyléther de propylène glycol, le monoéthyléther de diéthylène glycol. Ces compositions destinées à une application topique peuvent également contenir au moins un additif conventionnel ou un principe actif. Parmi ceux-ci, on peut notamment citer les filtres UV.A et UV.B comme les méthoxycinnamates et les dérivés de benzophénone, les anti-oxydants et/ou capteurs de radicaux libres tels que le DMSO, l'α-tocophérol, le BHA, le BHT, la superoxyde dismutase, les agents hydratants tels que l'urée, la glycérine, l'acide lactique, les hydroxyacides, la thiamorpholinone et ses dérivés et les dérivés de l'acide pyrrolidone carboxylique notamment ses sels de sodium et de potassium, les agents anti-inflammatoires stéroïdiens et non-stéroïdiens tels que l 'hydrocortisone, la β-méthasone, la dexaméthasone, l'acide acétyl salicylique, l'indométhacine, l'isoprofène, la vitamine D ou l'acide niflumique, et les anti-bactériens tels que ceux appartenant au groupe des macrolides, des pyranosides et des tétracyclines telles que l'érythromycine.The physiologically acceptable medium can consist of water or a mixture of water and a solvent or a mixture of solvents. Among the solvents which can be used, mention may in particular be made of lower C r C 4 alcohols such as ethanol, isopropanol, tert-butanol, alkylene glycols, alkylene glycol and dialkylene glycol alkyl ethers such as monoethyl ether d ethylene glycol, propylene glycol monomethyl ether, diethylene glycol monoethyl ether. These compositions intended for topical application can also contain at least one conventional additive or an active principle. Among these, mention may in particular be made of UV.A and UV.B filters such as methoxycinnamates and benzophenone derivatives, antioxidants and / or free radical scavengers such as DMSO, α-tocopherol, BHA, BHT, superoxide dismutase, hydrating agents such as urea, glycerin, lactic acid, hydroxy acids, thiamorpholinone and its derivatives and pyrrolidone carboxylic acid derivatives, in particular its sodium and potassium, steroidal and non-steroidal anti-inflammatory agents such as hydrocortisone, β-methasone, dexamethasone, acetyl salicylic acid, indomethacin, isoprofen, vitamin D or niflumic acid, and antibacterials such as those belonging to the group of macrolides, pyranosides and tetracyclines such as erythromycin.
Ces compositions peuvent également contenir des agents conservateurs, des agents stabilisants, des agents régulateurs de pH, des agents modificateurs de pression osmotique et des agents émulsifiants.These compositions may also contain preservatives, stabilizers, pH regulators, osmotic pressure modifiers and emulsifiers.
Ces compositions destinées à une application topique à base de 2,4-DPO peuvent se présenter sous différentes formes telles que par exemple sous forme de lotions, de gels, de mousses, de dispersions vésiculaires, de sprays ou de mousses aérosol.These compositions intended for topical application based on 2,4-DPO can be presented in different forms such as for example in the form of lotions, gels, mousses, vesicular dispersions, sprays or aerosol mousses.
Ces compositions peuvent également se présenter sous forme de compositions gélifiées ou épaissies. Parmi les compositions gélifiées, on peut en particulier citer celles, essentiellement aqueuses, gélifiées par des hétérobiopolysaccharides tels que la gomme de xanthane, les scléroglucanes ou les dérivés de cellulose et en particulier les éthers de cellulose, ou les compositions hydroalcooliques gélifiées par des polyhydroxyéthylacrylates ou méthacrylates. Parmi les compositions aqueuses épaissies, on peut citer celles obtenues en particulier à l'aide d'un acide polyacrylique réticulé par un agent polyfonctionnel tel que ceux commercialisés sous les dénominations de "Carbopol®" par la Société Goodrich. Il est cependant bien entendu possible d'utiliser comme agent épaississant tout agent habituellement employé en pharmacie ou en dermo-pharm acie.These compositions can also be in the form of gelled or thickened compositions. Among the gelled compositions, mention may in particular be made of those which are essentially aqueous, gelled with heterobiopolysaccharides such as xanthan gum, scleroglucans or cellulose derivatives and in particular cellulose ethers, or hydroalcoholic compositions gelled with polyhydroxyethylacrylates or methacrylates. Among the thickened aqueous compositions, there may be mentioned those obtained in particular using a polyacrylic acid crosslinked with a polyfunctional agent such as those sold under the names of "Carbopol®" by the company Goodrich. It is however of course possible to use as thickening agent any agent usually used in pharmacy or dermo-pharm acie.
Par voie topique, le 2,4-DPO est généralement appliqué sur les parties du corps à traiter à raison de 0,0001 à 5 mg/kg/jour et de préférence de 0,001 à 1 mg/kg/jour. Le traitement est généralement poursuivi pendant toute la période pendant laquelle se produit l'accumulation de collagène et peut être éventuellement poursuivi pendant 90 jours après celle-ci.Topically, 2,4-DPO is generally applied to the parts of the body to be treated at a rate of 0.0001 to 5 mg / kg / day and preferably from 0.001 to 1 mg / kg / day. The treatment is generally continued throughout the period during which the accumulation of collagen occurs and may possibly be continued for 90 days after this.
On peut également, selon l'invention, utiliser le 2,4-DPO pour la préparation de compositions thérapeutiques destinées à une administration par voie transdermique. La proportion en 2,4-DPO est alors généralement comprise entre 0,001 et 5 % et de préférence comprise entre 0,01 et 2 % par rapport au poids total de la composition. L'excipient utilisé dans ces compositions est généralement choisi parmi les copolymeres ou copolymeres vinyliques, additionnés éventuellement d'un promoteur de pénétration.It is also possible, according to the invention, to use 2,4-DPO for the preparation of therapeutic compositions intended for administration by transdermal route. The proportion of 2,4-DPO is then generally between 0.001 and 5% and preferably between 0.01 and 2% relative to the total weight of the composition. The excipient used in these compositions is generally chosen from vinyl copolymers or copolymers, optionally added with a penetration promoter.
Les compositions destinées à une application transdermique peuvent être notamment administrées à l'aide d'un système auto-collant adhérant sur la peau et assurant le passage continu, pendant au moins 24 heures, d'une quantité contrôlée de substance active, à travers la peau, dans la circulation sanguine.The compositions intended for transdermal application can in particular be administered using a self-adhesive system adhering to the skin and ensuring the continuous passage, for at least 24 hours, of a controlled quantity of active substance, through the skin, into the bloodstream.
Parmi ces systèmes, on peut notamment citer ceux décrits dans la demande FR-88.11685 (2.635.979) ainsi que ceux commercialisés par la Société Tilderm. Le 2,4-DPO peut être également utilisé pour la préparation de compositions thérapeutiques destinées à une administration par voie intradermique.Among these systems, mention may in particular be made of those described in application FR-88.11685 (2,635,979) as well as those sold by the company Tilderm. 2,4-DPO can also be used for the preparation of therapeutic compositions intended for administration by the intradermal route.
La proportion en 2,4-DPO est alors généralement comprise entre 0,0001 et 5 % en poids, et de préférence comprise entre 0,01 et 1 % en poids par rapport au poids total de la composition. Le 2,4-DPO est alors sous forme soluble dans un véhicule physiologiquement acceptable tel que du sérum physiologique.The proportion of 2,4-DPO is then generally between 0.0001 and 5% by weight, and preferably between 0.01 and 1% by weight relative to the total weight of the composition. 2,4-DPO is then in soluble form in a physiologically acceptable vehicle such as physiological saline.
Les compositions destinées à une administration intradermique peuvent comprendre en outre différents agents thérapeutiques tels que par exemple des agents antibactériens, des agents antioxydants et des anti-inflamatoires stéroïdiens et non stéroïdiens.The compositions intended for intradermal administration can also comprise various therapeutic agents such as, for example, antibacterial agents, antioxidant agents and anti-inflammatory drugs, steroid and non-steroid.
Le 2,4-DPO est généralement administré par voie intradermique à raison d'une dose inférieure ou égale à 5 mg/kg/jour, et de préférence comprise entre 0,0001 et 1 mg/kg/jour. Le traitement est généralement appliqué pendant toute la période durant laquelle se produit l'accumulation de collagène et peut être éventuellement poursuivi pendant 30 jours après celle-ci.2,4-DPO is generally administered intradermally at a dose less than or equal to 5 mg / kg / day, and preferably between 0.0001 and 1 mg / kg / day. The treatment is generally applied during the entire period during which the accumulation of collagen occurs and can possibly be continued for 30 days after this.
Bien qu'il ait été plus particulièrement fait référence ci-dessus à des compositions destinées à un usage pharmaceutique, il va de soi que celles-ci peuvent être formulées sous une forme plus appropriée pour un usage vétérinaire notamment dans le traitement d'équidés tels que le cheval. Les compositions selon l'invention quel que soit le mode d'administration ou l'usage auquel elles sont destinées sont préparées selon des méthodes connues.Although reference has been made more particularly above to compositions intended for pharmaceutical use, it goes without saying that these can be formulated in a form more suitable for veterinary use, especially in the treatment of equines such than the horse. The compositions according to the invention, whatever the mode of administration or the use for which they are intended, are prepared according to known methods.
On va maintenant donner à titre d'illustration les résultats d'études mettant en évidence l'efficacité du 2,4-DPO ainsi que divers exemples de compositions thérapeutiques. 1 - Etude de l'inhibition de l'expression des ARNm codant pour la lysyl hydroxylase (LH)We will now give by way of illustration the results of studies demonstrating the efficacy of 2,4-DPO as well as various examples of therapeutic compositions. 1 - Study of the inhibition of the expression of mRNAs coding for lysyl hydroxylase (LH)
A partir d'une culture de fibroblastes provenant de gaines conjonctives externes de cheveu humain au cinquième repiquage, on ensemence 2.105 fibroblastes dans des boîtes de Pétri de 60 mm de diamètre contenant un milieu de culture de type "Eagle", modifié Dulbecco et supplémenté par 2 mM de L-glutamine, 1 mM de pyruvate de sodium, 100 unités/ml de pénicilline G, 100 μg/ml de streptomycine S, 250 mg/ml d'amphotérine et 10 % de sérum de veau foetal commercialisé par la Société Gibco BRL. Après 24 heures de culture à 37°C dans une étuve à 95 % air/5 % C02, on remplace le milieu par un milieu analogue ne contenant toutefois pas de sérum de veau foetal. On incube ensuite les cellules à 37°C pendant 3 heures (figure 1A) ou 18 heures (figure 1B) en présence de 5 M de Minoxidil, de 5 mM de 2,4-DPO ou de 5 mM de sulfate de Minoxidil.2.10 5 fibroblasts are seeded in a 60 mm diameter petri dish containing a Dulbecco modified culture medium supplemented with a culture of fibroblasts originating from external connective sheaths of human hair on the fifth subculture. with 2 mM L-glutamine, 1 mM sodium pyruvate, 100 units / ml of penicillin G, 100 μg / ml of streptomycin S, 250 mg / ml of amphoterine and 10% fetal calf serum marketed by the Company Gibco BRL. After 24 hours of culture at 37 ° C. in an oven at 95% air / 5% C0 2 , the medium is replaced by an analogous medium, however containing no fetal calf serum. The cells are then incubated at 37 ° C. for 3 hours (FIG. 1A) or 18 hours (FIG. 1B) in the presence of 5 M of Minoxidil, 5 mM of 2,4-DPO or 5 mM of Minoxidil sulfate.
Selon la méthode décrite dans "Short protocoles in molecular biology, Harvard médical school J. Willey and sons publisher, 1992", on extrait l'ARN total de chacune des préparations cellulaires puis quantifie celui-ci par mesures spectrophotométriques UV à 280 nm.According to the method described in "Short protocols in molecular biology, Harvard medical school J. Willey and sons publisher, 1992", the total RNA of each of the cell preparations is extracted and then quantified thereof by UV spectrophotometric measurements at 280 nm.
Pour permettre l'analyse de l'expression des ARNm, on effectue une amplification de ceux-ci par une réaction de polymérisation en chaîne (PCR). A partir de 2 μg d'ARN total obtenus précédemment pour chaque préparation cellulaire, on synthétise in vitro de l'ADN complémentaire à l'aide d'un kit de transcription réverse commercialisé sous la dénomination de "First Strand C-DNA Synthesis kit" par la Société Pharmacia LKB Biotechnology AB. Une fraction aliquote de l'ADN complémentaire obtenu précédemment est ensuite amplifiée par la méthode de PCR proprement dite en présence des amorces spécifiques de la lysyl hydroxylase (LH) et de la prolyl hydroxylase (PH) suivantes : amorce LH sens : 5'GAAATGGGCCATGTGAGAGCG3' amorce LH antisens : 5 GTGGATGACAATAGTCGGCACG3' amorce PH sens : 5'GTGGATGGAACAAGCCCTAAGGC3' amorce PH antisens : 5'CCTCCCCACGGCACAGCATTTCG3', pour un volume final de 50 μl.To allow analysis of the expression of the mRNAs, the latter are amplified by a polymerase chain reaction (PCR). From 2 μg of total RNA obtained previously for each cell preparation, complementary DNA is synthesized in vitro using a reverse transcription kit marketed under the name of "First Strand C-DNA Synthesis kit" by Pharmacia LKB Biotechnology AB. An aliquot fraction of the complementary DNA obtained previously is then amplified by the PCR method proper in the presence of the following primers specific for lysyl hydroxylase (LH) and prolyl hydroxylase (PH): primer LH sense: 5'GAAATGGGCCATGTGAGAGCG3 ' antisense LH primer: 5 GTGGATGACAATAGTCGGCACG3 'sense PH primer: 5'GTGGATGGAACAAGCCCTAAGGC3' antisense PH primer: 5'CCTCCCCACGGCACAGCATTTCG3 ', for a final volume of 50 μl.
20 μl du mélange obtenu après PCR sont déposés sur un gel d'électrophorèse à20 μl of the mixture obtained after PCR are deposited on an electrophoresis gel at
2 % d'agarose en présence de 0,5 μg/ml de bromure d'éthidium et du tampon d'électrophorèse Tris acétate EDTA (TAE) lx. Après migration pendant 1 heure, sous un champ électrique de 100 V, l'intensité des bandes correspondant aux ARNm codant respectivement pour la lysyl hydroxylase et la prolyl hydroxylase est analysée et quantifiée au moyen d'un analyseur d'images et du logiciel commercialisé sous la dénomination de "Bioprofil®" par la Société Vilbert Lourmat.2% agarose in the presence of 0.5 μg / ml of ethidium bromide and the Tris acetate EDTA acetate buffer (TAE) 1x. After migration for 1 hour, under an electric field of 100 V, the intensity of the bands corresponding to the mRNAs coding respectively for lysyl hydroxylase and prolyl hydroxylase is analyzed and quantified using an image analyzer and software marketed under the name "Bioprofil®" by the Vilbert Lourmat Company.
Selon le même mode opératoire que décrit précédemment, on mesure également les taux d'expression relative des ARNm codant pour la lysyl hydroxylase et pour la prolyl hydroxylase après 3 heures et 18 heures de culture de fibroblastes en absence de tout traitement.According to the same operating procedure as described above, the relative expression levels of the mRNAs coding for lysyl hydroxylase and for prolyl hydroxylase are also measured after 3 hours and 18 hours of fibroblast culture in the absence of any treatment.
Les résultats sont présentés dans les figures 1A et 1B.The results are presented in Figures 1A and 1B.
On constate donc que l'incubation de fibroblastes pendant 3 heures en présence de Minoxidil ou de Minoxidil sulfate réduit le taux d'expression relative des ARNm codant pour la lysyl hydroxylase, celui-ci étant alors de 0,75.It is therefore found that the incubation of fibroblasts for 3 hours in the presence of Minoxidil or Minoxidil sulfate reduces the relative expression rate of the mRNAs coding for lysyl hydroxylase, the latter then being 0.75.
Après 3 heures d'incubation en présence de 2,4-DPO, le taux d'expression relative des ARNm codant pour la lysyl hydroxylase est de 0,55.After 3 hours of incubation in the presence of 2,4-DPO, the relative expression rate of the mRNAs coding for the lysyl hydroxylase is 0.55.
Le 2,4-DPO inhibe donc plus l'expression des ARNm codant pour la lysyl hydroxylase que le Minoxidil ou que son analogue sulfaté.2,4-DPO therefore inhibits the expression of mRNAs coding for lysyl hydroxylase more than Minoxidil or its sulphated analogue.
On observe des résultats analogues après 18 heures de culture en présence des différents inhibiteurs testés.Similar results are observed after 18 hours of culture in the presence of the various inhibitors tested.
Par ailleurs, après 3 heures de culture en présence de Minoxidil ou de Minoxidil sulfate, le taux d'expression relative des ARNm codant pour la prolyl hydroxylase augmente, atteignant respectivement 1,25 et 1,85.Furthermore, after 3 hours of culture in the presence of Minoxidil or Minoxidil sulfate, the relative expression rate of the mRNAs coding for prolyl hydroxylase increases, reaching 1.25 and 1.85 respectively.
Après 3 heures d'incubation en présence de 2,4-DPO, le taux d'expression relative des ARNm codant pour la prolyl hydroxylase est également plus élevé, celui-ci étant alors de l'ordre de 1,3.After 3 hours of incubation in the presence of 2,4-DPO, the relative expression rate of the mRNAs coding for prolyl hydroxylase is also higher, this then being of the order of 1.3.
Après 18 heures de culture en présence de Minoxidil, de Minoxidil sulfate ou de 2,4-DPO, les taux d'expression relative des ARNm codant pour la prolyl hydroxylase sont respectivement de 1,6, 1,3 et 1,15.After 18 hours of culture in the presence of Minoxidil, Minoxidil sulfate or 2,4-DPO, the relative expression levels of the mRNAs coding for prolyl hydroxylase are 1.6, 1.3 and 1.15 respectively.
On n'observe donc pas d'inhibition du taux d'expression relative des ARNm codant pour la prolyl hydroxylase en réponse à ces trois composés.There is therefore no inhibition of the rate of relative expression of the mRNAs coding for prolyl hydroxylase in response to these three compounds.
Les composés testés présentent donc une activité inhibitrice spécifique de la lysyl hydroxylase. II - Etude de l'effet du 2,4-DPO sur le réseau de colla ène présent dans la matrice extracellulaire de fibroblastes en cultureThe compounds tested therefore exhibit a specific inhibitory activity on lysyl hydroxylase. II - Study of the effect of 2,4-DPO on the collagen network present in the extracellular matrix of fibroblasts in culture
A une culture primaire de fibroblastes dermiques humains provenant d'une plastie mammaire, dans un milieu DMEM supplémenté par 10 % de sérum de veau foetal, on ajoute 10 μM du 2,4-DPO.To a primary culture of human dermal fibroblasts originating from a breast plasty, in a DMEM medium supplemented with 10% of fetal calf serum, 10 μM of 2,4-DPO is added.
Après trois jours, on lyse les cellules par un choc hypoosmotique et fixe le dépôt de collagène par une solution à 5 % de glutaraldéhyde.After three days, the cells are lysed by hypoosmotic shock and the deposition of collagen is fixed with a 5% solution of glutaraldehyde.
On observe ensuite la matrice extracellulaire des fibroblastes à l'aide d'un microscope électronique à balayage.The fibroblast extracellular matrix is then observed using a scanning electron microscope.
On observe également en microscopie électronique à balayage la matrice extracellulaire d'une culture primaire de fibroblastes non traités.The extracellular matrix of a primary culture of untreated fibroblasts is also observed by scanning electron microscopy.
Ces photographies sont présentées dans les Figures 2 et 3. Comme on peut le constater d'après les photos des Figures 2 et 3, la matrice extracellulaire de fibroblastes non traités présente de gros amas fibreux entourant de larges plages dépourvues de réseau de collagène, tandis que la matrice extracellulaire des fibroblastes traités au 2,4-DPO présente une organisation beaucoup plus régulière dans laquelle on n'observe pas de gros amas fibreux et où la taille des plages dépourvues de réseau de collagène est beaucoup plus réduite. L'application du 2,4-DPO sur une culture de fibroblastes entraine donc une réorganisation spatiale en micro-réseau des fibres de collagène. These photographs are presented in Figures 2 and 3. As can be seen from the photos in Figures 2 and 3, the extracellular matrix of untreated fibroblasts has large fibrous clusters surrounding large areas lacking a collagen network, while that the extracellular matrix of fibroblasts treated with 2,4-DPO has a much more regular organization in which no large fibrous clusters are observed and in which the size of the patches lacking a collagen network is much smaller. The application of 2,4-DPO to a culture of fibroblasts therefore results in a spatial reorganization into a micro-network of the collagen fibers.
EXEMPLES DE COMPOSITIONS THERAPEUTIQUESEXAMPLES OF THERAPEUTIC COMPOSITIONS
EXEMPLE 1 : Crème dermiqueEXAMPLE 1 Dermal cream
On prépare une crème dermique par mélange des ingrédients suivants :A dermal cream is prepared by mixing the following ingredients:
- 2,4-DPO 0,5 g- 2,4-DPO 0.5 g
- Ceteareth 30 7 g- Ceteareth 30 7 g
- Stéarate de glycéryle 2 g - Alcool cétylique 1,5 g- Glyceryl stearate 2 g - Cetyl alcohol 1.5 g
- Polydiméthylsiloxane 1,5 g- Polydimethylsiloxane 1.5 g
- Huile de paraffine 15 g- Paraffin oil 15 g
- Glycérine codex pure 20 g- Glycerin codex pure 20 g
- Conservateurs q.s. - Eau déminéralisée q.s.p. 100 g- Preservatives q.s. - Demineralized water q.s.p. 100g
EXEMPLE 2 : Lotion dermique à pulvériserEXAMPLE 2 Dermal Lotion to Spray
On prépare une lotion dermique à pulvériser par mélange des ingrédients suivants :A dermal lotion to be sprayed is prepared by mixing the following ingredients:
- 2,4-DPO 0,25 g- 2,4-DPO 0.25 g
- Ethanol 30 g- Ethanol 30 g
- Eau déminéralisée q.s.p. 100 g- Demineralized water q.s.p. 100g
EXEMPLE 3 : Solution injectableEXAMPLE 3 Solution for injection
On prépare une solution injectable par voie intradermique par mélange des ingrédients suivants :An injectable solution is prepared intradermally by mixing the following ingredients:
- 2,4-DPO 0,7 mg- 2,4-DPO 0.7 mg
- Sérum physiologique (NaCl 9 g/H20 qsp 100 ml) q.s.p. 1 ml - Physiological serum (NaCl 9 g / H 2 0 qs 100 ml) qs 1 ml

Claims

R E V E N D I C A T I O N S
1. Utilisation en tant que substance active du 2,4-diamino pyrimidine 3-oxyde (2,4-DPO) ou de l'un de ses sels physiologiquement acceptables pour la préparation d'une composition, thérapeutique, à usage pharmaceutique ou vétérinaire, destinée au traitement des désordres de la maturation et de la structuration du collagène.1. Use as active substance of 2,4-diamino pyrimidine 3-oxide (2,4-DPO) or one of its physiologically acceptable salts for the preparation of a therapeutic composition for pharmaceutical or veterinary use , intended for the treatment of disorders of maturation and structuring of collagen.
2. Utilisation selon la revendication 1, caractérisée par le fait que les sels sont choisis parmi ceux d'addition d'un acide pris dans le groupe constitué par l'acide sulfurique, chlorhydrique, phosphorique, acétique, benzoïque, salicylique, glycolique, acéturique, suçcinique, nicotinique, tartrique, maléïque, méthane sulfonique, picrique et lactique.2. Use according to claim 1, characterized in that the salts are chosen from those of addition of an acid taken from the group consisting of sulfuric, hydrochloric, phosphoric, acetic, benzoic, salicylic, glycolic, aceturic acid , succinic, nicotinic, tartaric, maleic, methane sulfonic, picric and lactic.
3. Utilisation selon l'une quelconque des revendications précédentes, caractérisée par le fait que ladite composition se présente sous une forme administrable par voie topique, transdermique ou intradermique. 4. Utilisation selon l'une quelconque des revendications précédentes, caractérisée par le fait que ladite composition est sous une forme administrable par voie topique, la proportion en 2,3. Use according to any one of the preceding claims, characterized in that the said composition is in a form which can be administered topically, transdermally or intradermally. 4. Use according to any one of the preceding claims, characterized in that the said composition is in a form which can be administered topically, the proportion in 2,
4-DPO étant comprise entre 0,0001 et 5 % en poids par rapport au poids total de la composition.4-DPO being between 0.0001 and 5% by weight relative to the total weight of the composition.
5. Utilisation selon la revendication 4, caractérisée par le fait que la proportion en 2,4-DPO est comprise entre 0,01 et 2 % en poids par rapport au poids total de la composition.5. Use according to claim 4, characterized in that the proportion e n 2,4-DPO is between 0.01 and 2% by weight relative to the total weight of the composition.
6. Utilisation selon l'une quelconque des revendications 1 à 3, caractérisée par le fait que ladite composition est sous une forme administrable par voie transdermique, la proportion en 2,4-DPO étant comprise entre 0,001 et 5 % en poids par rapport au poids total de la composition.6. Use according to any one of claims 1 to 3, characterized in that the said composition is in a form which can be administered transdermally, the proportion of 2,4-DPO being between 0.001 and 5% by weight relative to the total weight of the composition.
7. Utilisation selon la revendication 6, caractérisée par le fait que la proportion en 2,4-DPO est comprise entre 0,01 et 2 % en poids par rapport au poids total de la composition.7. Use according to claim 6, characterized in that the proportion of 2,4-DPO is between 0.01 and 2% by weight relative to the total weight of the composition.
8. Utilisation selon l'une quelconque des revendications 1 à 3, caractérisée par le fait que ladite composition est sous une forme administrable par voie intradermique, la proportion en 2,4-DPO étant comprise entre 0,0001 et 5 % en poids par rapport au poids total de la composition.8. Use according to any one of claims 1 to 3, characterized in that the said composition is in a form which can be administered intradermally, the proportion of 2,4-DPO being between 0.0001 and 5% by weight. relative to the total weight of the composition.
9. Utilisation selon la revendication 8, caractérisée par le fait que la proportion en 2,4-DPO est comprise entre 0,01 et 1 % en poids par rapport au poids total de la composition. 9. Use according to claim 8, characterized in that the proportion of 2,4-DPO is between 0.01 and 1% by weight relative to the total weight of the composition.
10. Utilisation selon l'une quelconque des revendications précédentes, caractérisée par le fait que ladite composition est destinée à traiter les désordres de la maturation du collagène chez l'homme.10. Use according to any one of the preceding claims, characterized in that the said composition is intended for treating disorders of the maturation of collagen in humans.
11. Utilisation selon l'une quelconque des revendications 1 à 9, caractérisée par le fait que ladite composition est destinée à traiter les désordres de la maturation du collagène chez l'animal.11. Use according to any one of claims 1 to 9, characterized in that the said composition is intended for treating disorders of the maturation of collagen in animals.
12. Utilisation selon la revendication 11, caractérisé par le fait que l'animal est un équidé. 12. Use according to claim 11, characterized in that the animal is an equine.
PCT/FR1995/001197 1994-09-19 1995-09-19 Use of 2,4-diamino pyrimidine 3-oxide or a salt thereof for treating collagen maturation and structuring disorders WO1996009048A1 (en)

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BR9508841A BR9508841A (en) 1994-09-19 1995-09-19 Use of 2,4-diamino pyrimidine 3-oxide or one of its salts in the treatment of collagen maturation and structuring disorders
AU34765/95A AU691336B2 (en) 1994-09-19 1995-09-19 Use of 2,4-diamino pyrimidine 3-oxide or a salt thereof for treating collagen maturation and structuring disorders
CA002199995A CA2199995C (en) 1994-09-19 1995-09-19 Use of 2,4-diamino pyrimidine 3-oxide or a salt thereof for treating collagen maturation and structuring disorders
US08/809,950 US5846552A (en) 1994-09-19 1995-09-19 Use of 2,4-diaminopyrimidine 3-oxide or a salt thereof for treating collagen maturation and structuring disorders
PL95319279A PL186385B1 (en) 1994-09-19 1995-09-19 Application of 2,4-diamino pyrimidine 3-oxide or one of its salts in treating maturation and collagen structurisation disturbances
MX9701996A MX9701996A (en) 1994-09-19 1995-09-19 Use of 2,4-diamino pyrimidine 3-oxide or a salt thereof for treating collagen maturation and structuring disorders.
HU9701236A HU223143B1 (en) 1994-09-19 1995-09-19 Use of 2,4-diamino pyrimidine 3-oxide or salts thereof for preparing pharmaceutical composition for treating collagen maturation and structruring disorders
AT95931260T ATE213414T1 (en) 1994-09-19 1995-09-19 USE OF 2,4-DIAMINOPYRIMIDINE-3-OXYDE AND/OR ITS SALTS FOR TREATING DISORDERS OF COLLAGEN MATURATION OR STRUCTURING
CZ97842A CZ284476B6 (en) 1994-09-19 1995-09-19 Use of 2,4-diaminopyrimidine-3-oxide or some of its salts for treating disorders of ripening and structure formation of collagen
JP8510645A JP2945482B2 (en) 1994-09-19 1995-09-19 Use of 2,4-diaminopyrimidine-3-oxide or a salt thereof for the treatment of collagen maturation and structural disorders
EP95931260A EP0783307B1 (en) 1994-09-19 1995-09-19 Use of 2,4-diamino pyrimidine 3-oxide or a salt thereof for treating collagen maturation and structuring disorders
DE69525539T DE69525539T2 (en) 1994-09-19 1995-09-19 USE OF 2,4-DIAMINOPYRIMIDIN-3-OXYD AND / OR ITS SALTS FOR TREATING COLLAGEN RIPING OR STRUCTURING DISORDERS
KR1019970701754A KR100250939B1 (en) 1994-09-19 1995-09-19 The composition for treating collagen maturation and structuring disorders
DK95931260T DK0783307T3 (en) 1994-09-19 1995-09-19 Use of 2,4-diaminopyrimidine-3-oxide or a salt thereof in the treatment of disorders in the maturation and structuring of collagen
NO19971182A NO311784B1 (en) 1994-09-19 1997-03-14 Use of 2,4-diaminopyrimidine-3-oxide or a salt thereof for the preparation of a pharmaceutical composition for the treatment of collagen maturation and structuring disorders
FI971127A FI971127A0 (en) 1994-09-19 1997-03-18 Use of 2,4-diaminopyrimidine-3-oxide or one of its salts for the treatment of collagen maturation and construction disorders

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EP2149368A1 (en) 2008-07-29 2010-02-03 L'oreal Cosmetic use of microorganism(s) for the treatment of scalp disorders
US7763587B2 (en) 2002-06-13 2010-07-27 L'oreal S.A. Derivative of glucose and of vitamin F, compositions comprising it, uses and preparation process
WO2011051633A2 (en) 2009-10-30 2011-05-05 L'oreal Use of a punica granatum extract to fight against the whitening of the hair
FR3130153A1 (en) 2021-12-15 2023-06-16 L'oreal Use of at least one pyrimidine 3-oxide derivative to reinforce the barrier function of the skin

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EP1946756A1 (en) * 2007-01-17 2008-07-23 Revotar Biopharmaceuticals AG Use of entacapone in cosmetic, dermatological and pharmaceutical compositions
CN104398418A (en) * 2014-11-06 2015-03-11 陈爱华 Hair-loss-resistant hair conditioner

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Cited By (10)

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US7763587B2 (en) 2002-06-13 2010-07-27 L'oreal S.A. Derivative of glucose and of vitamin F, compositions comprising it, uses and preparation process
US7795230B2 (en) 2002-06-13 2010-09-14 L'oreal S.A. Derivative of glucose and of vitamin F, compositions comprising it, uses and preparation process
US7977318B2 (en) 2002-06-13 2011-07-12 L'oreal S.A. Derivative of glucose and of vitamin F, compositions comprising it, uses and preparation process
US7326717B2 (en) 2003-05-06 2008-02-05 L'oreal Pyrimidine n-oxide compounds for stimulating the growth of keratin fibers and/or reducing loss thereof
EP1607083A1 (en) 2004-06-16 2005-12-21 L'oreal Method to promote the penetration of a cosmetic active ingredient and the composition therefor
US7300649B2 (en) 2005-02-11 2007-11-27 Genepharm, Inc. Cosmetic and cosmeceutical compositions for restoration of skin barrier function
JP2008001693A (en) * 2006-06-20 2008-01-10 L'oreal Sa Use of ellagic acid for treating canities
EP2149368A1 (en) 2008-07-29 2010-02-03 L'oreal Cosmetic use of microorganism(s) for the treatment of scalp disorders
WO2011051633A2 (en) 2009-10-30 2011-05-05 L'oreal Use of a punica granatum extract to fight against the whitening of the hair
FR3130153A1 (en) 2021-12-15 2023-06-16 L'oreal Use of at least one pyrimidine 3-oxide derivative to reinforce the barrier function of the skin

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MX9701996A (en) 1997-06-28
EP0783307B1 (en) 2002-02-20
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PL186385B1 (en) 2004-01-30
DE69525539T2 (en) 2002-09-26
ATE213414T1 (en) 2002-03-15
PL319279A1 (en) 1997-08-04
JP2945482B2 (en) 1999-09-06
US5846552A (en) 1998-12-08
HU223143B1 (en) 2004-03-29
NO971182D0 (en) 1997-03-14
CA2199995A1 (en) 1996-03-28
FR2724561B1 (en) 1996-12-13
EP0783307A1 (en) 1997-07-16
RU2153874C2 (en) 2000-08-10
DK0783307T3 (en) 2002-06-03
CN1070702C (en) 2001-09-12
HUT76796A (en) 1997-11-28
AU3476595A (en) 1996-04-09
NO311784B1 (en) 2002-01-28
FI971127A (en) 1997-03-18
NO971182L (en) 1997-05-14
DE69525539D1 (en) 2002-03-28
FR2724561A1 (en) 1996-03-22
CA2199995C (en) 2002-01-15
CN1159755A (en) 1997-09-17
JPH10506886A (en) 1998-07-07
PT783307E (en) 2002-07-31
ES2171550T3 (en) 2002-09-16
CZ84297A3 (en) 1997-08-13
AU691336B2 (en) 1998-05-14
KR100250939B1 (en) 2000-05-01
CZ284476B6 (en) 1998-12-16
FI971127A0 (en) 1997-03-18
KR970705998A (en) 1997-11-03

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